UNIT 3. CHEMISTRY The objective of Unit 3 is to advance Hit compounds to Probes that have sufficient potency, selectivity, physicochemical, and pharmacological properties to be useful as research tools. Our Chemistry Unit uses a full complement of approaches to design and synthesize optimized Probe compounds, including: (1) modern medicinal chemistry;(2) cheminformatics, and computational chemistry and modeling;(3) advanced microfluidic synthesis technology;(4) innovative NMR-based methods for compound optimization utilizing chemical fragment linking strategies;and (5) exploratory pharmacology including in vitro assays that help both triage hits early and assist with the compound optimization process. Altogether, the chemical synthesis and supporting capabilities of the Burnham Center are among the most diverse and advanced of the present MLSCN Centers. This proposal builds on the Chemistry Unit's strong performance during the MLSCN Phase. We describe progress to date and plans to undertake a minimum of 25 Probe production projects annually to improve the potency and optimize the physicochemical properties of Hit compounds, delivering at least 15 new Probes per year.